Protein-polymer-drug conjugates

Abstract

A polymeric scaffold useful for conjugating with a protein based recognition-molecule (PBRM) to form a PBRM-polymer-drug conjugate is described herein. The scaffold includes one or more terminal maleimido groups. Also disclosed is a PBRM-polymer-drug conjugate prepared from the scaffold. Compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions are also described.

What is claimed is: 
     
         1 . A therapeutic drug and targeting conjugate useful in anti-neoplastic therapies comprising:
 (a) a ligand (LG) which comprises an immunoglobulin or functional fragment thereof which targets human oncofetal protein 5T4, the ligand having bound thereto m 5  of polymeric scaffolds of (b), wherein m 5  is one to about ten;   (b) a polymeric scaffold comprising poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) which has a molecular weight ranging from about 2 kDa to about 40 kDa, wherein the polymeric scaffold comprises randomly arranged monomeric units m, m 1 , m 2 , m 3a  and m 3b , defined as follows:   (i) m 3a :   
       
         
           
           
               
               
           
         
         wherein m 3a  is absent or 1 to about 17 monomeric m 3a  units are present in the polymer scaffold, and in each unit, X a  and X b  are independently selected from (A) one is H and the other is a maleimido blocking moiety, or (B) X a  and X b , together with the carbon atoms to which they are attached form a carbon-carbon double bond; 
         (ii) m 3b : 
       
       
         
           
           
               
               
           
         
       
       wherein the sulfide bond forms the point of attachment to the ligand, and wherein 1 to about 8 monomer m 3b  units are present in the polymeric scaffold, provided that the sum of m 3a  and m 3b  is 1 to 18, and wherein the sulfur atom is part of the ligand,
 (iii) m: 
 
       
         
           
           
               
               
           
         
         wherein 1 to about 300 monomer m units are present in the polymeric scaffold; 
         (iv) m 1 : 
       
       
         
           
           
               
               
           
         
       
       wherein 1 to about 140 monomeric m 1  units are present in the polymer scaffold;
 (v) m 2 : 
 
       
         
           
           
               
               
           
         
       
       wherein 1 to about 40 monomeric m 2  units are present in the polymer scaffold;
 wherein in each of the monomeric units m, m 1 , m 2 , m 3a , and m 3b , X is CH 2 , O or NH, 
 the sum of m, m 1 , m 2 , m 3a , and m 3b  ranges from about 15 to about 300, and wherein 
 each occurrence of D independently is a therapeutic agent having a molecular weight of ≤5 kDa, and the 
 
       
         
           
           
               
               
           
         
       
       between D and the carbonyl group denotes direct or indirect attachment of D to the carbonyl group,
 wherein m 5  is 2 to 8, 
 wherein m 5  is 2 to 4, 
 wherein D is independently selected from the group consisting of (a) an auristatin and its analogs; (b) a calicheamicin and its derivatives; (c) duocarmycin and its analogs; (d) SN38, and (e) pyrrolobenzodiazepine and its analogs, 
 wherein the duocarmycin or analogs thereof is selected from the group consisting of duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, duocarmycin SA, CC-1065, adozelesin, bizelesin, and carzelesin.